Introduction. The long-term goal of our studies is to determine if, and to what extent, a multi-mineral product (Aquamin) could have beneficial impact on individuals with ulcerative colitis (UC). As a step toward achieving that goal, we carried out a 180-day biomarker trial in patients with UC in remission or at the mild stage. Approach. A total of 28 subjects were included in the study. Each was randomized to receive either Aquamin for 180 days or placebo for the first 90 days. At day-90, placebo subjects crossed over to Aquamin for the final 90 days. At days-0, -90 and -180, serum samples were assessed for alkaline phosphatase (ALP), intestine-specific ALP (ALPI), C-reactive protein (CRP) and for biomarkers of bone turnover (osteocalcin, TRAP5b and bone-specific ALP [e.g., BALP]). Stool specimens were assessed for fecal calprotectin at the same time points and colon biopsies were examined histologically. Each subject underwent DEXA scanning (day-0 and -180 only). In addition, a mass spectrometry-based proteomic assessment was performed using colon biopsy specimens obtained at each time point. Results. Subjects receiving Aquamin for the complete 180-day period (a total of 12) demonstrated improvement in all biomarkers; this was not seen in the placebo group (16 subjects). Subjects who received Aquamin for 90-days were intermediary in their responses. Subjects receiving Aquamin for 180-days also demonstrated increases in bone mineral density (BMD) and bone mineral content (BMC) resulting in a statistically-significant increase in the hip strength index over the period of treatment. This was accompanied by increases in osteocalcin and TRAP5b and by a decrease in BALP. The proteomic screen demonstrated up-regulation of multiple gut barrier proteins, cell surface transporter molecules and certain proteins with anti-inflammatory potential in response to Aquamin. Aquamin treatment also led to down-regulation of several proteins associated with the pro-inflammatory state. Conclusion. These findings suggest the potential value of multi-mineral intervention (Aquamin) as a low-cost, non-toxic adjuvant therapy for mild UC or for individuals with UC in remission. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03869905 ### Funding Statement This investigator-initiated trial was supported through discretionary funds (JV) provided by Marigot Inc. as a gift to the University of Michigan, as well as the University of Michigan Pandemic Research Recovery (PRR) funding awarded to MA, and funding from the American Society for Investigative Pathology (ASIP) Summer Research Opportunity Program in Pathology (SROPP) to MA. None of these entities played any role in or had any influence on the research activities (i.e., study design, recruitment, data collection, data interpretation, or data dissemination). This study also utilized services at the University of Michigan supported by NIH funding (UM1TR004404 to the Michigan Institute for Clinical and Health Research). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The interventional study was conducted with FDA approval of Aquamin as an Investigational New Drug (IND#141600) and with oversight by the Institutional Review Board at the University of Michigan Medical School (IRBMED). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes - All data produced in the present study are available upon reasonable request to the authors - All data produced in the present work are contained in the manuscript - All generated proteomic data will be made publicly available in an online repository following the manuscript's publication.

From longstanding techniques like enzyme-linked immunosorbent assay (ELISA) to modern next-generation sequencing, many of the most sensitive and specific biomarker detection assays require capture of the analyte at a surface. While surface-based assays provide advantages, including the ability to reduce background by washing away excess reagents and/or increase specificity through analyte-specific capture probes, the limited efficiency of capture from dilute solution often restricts assay sensitivity to the femtomolar-to-nanomolar range. Although assays for many nucleic acid analytes can decrease limits of detection (LODs) to the subfemtomolar range using polymerase chain reaction, such amplification may introduce biases, errors, and an increased risk of sample cross-contamination. Furthermore, many analytes cannot be amplified easily, including short nucleic acid fragments, epigenetic modifications, and proteins. To address the challenge of achieving subfemtomolar LODs in surface-based assays without amplification, we exploit an aqueous two-phase system (ATPS) to concentrate target molecules in a smaller-volume phase near the assay surface, thus increasing capture efficiency compared to passive diffusion from the original solution. We demonstrate the utility of ATPS-enhanced capture via single molecule recognition through equilibrium Poisson sampling (SiMREPS), a microscopy technique previously shown to possess >99.9999% detection specificity for DNA mutations but an LOD of only ∼1-5 fM. By combining ATPS-enhanced capture with a Förster resonance energy transfer (FRET)-based probe design for rapid data acquisition over many fields of view, we improve the LOD ∼ 300-fold to <10 aM for an EGFR exon 19 deletion mutation. We further validate this ATPS-assisted FRET-SiMREPS assay by detecting endogenous exon 19 deletion molecules in cancer patient blood plasma.

The use of social media among surgeons is increasing in the professional domain as a result of the benefits of rapid communication for advertising, professional development, advocacy, and innovation. Social media allows for collaboration and consultation on cases that may be difficult or uncommon, drawing on collective wisdom but also bypassing traditional privacy protections and other regulatory firewalls. The expanded access that comes with social media produces challenges, including the management of information dissemination and ensuing perceptions, the risk of biased patient/research participant recruitment, the potential for overlap between personal and professional lives, and the precarious nature of self-interest in professional social media use. The ethics of surgical innovation in the context of social media has not been extensively discussed. The nature of social media favors attention grabbing, sensationalized content. Innovation is inherently sensational and demands attention. The alignment of these intrinsic characteristics forms a basis for its appeal and contagion on social media. Despite strict regulatory clinical research environment, many surgical innovations and subsequent evolution in practice arise from a longitudinal surgical culture of trial and error that happens every day. The difficulty in distinguishing innovation from research and the precarious nature of interactions found on social media create a unique ethical dilemma to be addressed for the innovative surgeon. Therefore, the use of social media in surgical innovation thus requires a more robust ethical analysis.

Background: In facial reanimation via microneurovascular muscle transfer, dual-nerve reinnervation of the muscle capitalizes on the synergistic effects of spontaneous motion from cross facial nerve grafting (CFNG) and increased excursion from masseteric nerve transfer. Two-stage approaches that delay masseteric nerve transfer until the time of the muscle flap increase spontaneity by maximizing muscle reinnervation from the CFNG. While this 2-stage, dual-nerve approach has been described in adults, we present a series of pediatric patients who underwent this reconstructive technique. Methods: We retrospectively reviewed all pediatric patients who underwent 2-stage, dual-nerve reconstruction with CFNG and ipsilateral masseteric nerve transfers. Procedures were performed between 2004 and 2016 by 2 surgeons at a single centre. Degree of facial paralysis before and after surgical intervention was measured using House-Brackmann scores. Results: Nine patients with a mean age of 8.6 (range: 5-15 years) years at time of surgery underwent 2-stage, dual-nerve reconstruction. Average time between CFNG and transfer of the free gracilis with masseteric nerve transfer was 13.3 (SD 2.4) months. Mean follow-up was 27.3 months (SD 25.7). Patients demonstrated initiation of voluntary movement on paralyzed side by 3.6 months (SD 0.6) on average, with 3 patients demonstrating spontaneous movement at 3 months. Conclusion: The 2-stage, dual innervation technique using CFNG and delayed ipsilateral masseteric nerve transfer with a free gracilis is a promising reconstructive option to maximize spontaneous expression in pediatric patients. Validated, objective scoring systems for excursion are needed before meaningful comparisons can be made to other reconstructive strategies.

BACKGROUND:The traditional definition of cure after parathyroidectomy (PTX) for primary hyperparathyroidism is normocalcemia. Our hypothesis was that early postoperative levels of serum calcium and parathyroid hormone after PTX would have predictive value for later recurrence.METHODS:We performed a retrospective study of 1,146 patients with primary hyperparathyroidism who underwent PTX and had long-term biochemical follow-up. The first postoperative serum level of calcium and parathyroid hormone values were used to categorize patients into the following four early biochemical response groups: (1) complete response (normal calcium and normal parathyroid hormone), (2) partial response with hyperparathormonemia (normal calcium and increased parathyroid hormone), (3) partial response with hypercalcemia (increased calcium and normal parathyroid hormone), and (4) non-response (increases in both calcium and parathyroid hormone). Incidences of recurrent hypercalcemia and recurrent primary hyperparathyroidism >6 months after operation were then analyzed.RESULTS:The overall rate of any elevated serum levels of calcium and any increase in serum levels of parathyroid hormone during >6-month follow-up was 9.8% (112 of 1146), with 6.6% (57 of 861) for group 1, 27% (35 of 129) for group 2, and 16% (20 of 127) for group 3 (P < .02). Partial biochemical responses with either increased serum calcium or increased parathyroid hormone levels were the strongest predictors of any episode of increased serum levels of calcium after 6 months and was associated with 2.7× to 4.3× the risk of recurrent primary hyperparathyroidism, respectively.CONCLUSION:This study demonstrates the importance of measuring parathyroid hormone in the early postoperative period to better predict later recurrent primary hyperparathyroidism.

PURPOSE:Early referral of neonatal brachial plexus palsy (NBPP) patients to multidisciplinary clinics is critical for timely diagnosis, treatment, and improved functional outcomes. In Saudi Arabia, inadequate knowledge regarding NBPP is a reason for delayed referral. We aimed to evaluate the knowledge of North American healthcare providers (HCPs) regarding the diagnosis, management, and prognosis of NBPP.METHODS:A 12-question survey regarding NBPP was distributed via electronic and paper formats to North American providers from various referring and treating specialties. NBPP knowledge was compared between Saudi Arabian vs. North American providers, referring vs. treating specialties, academic vs. community hospitals, and providers with self-reported confidence vs. nonconfidence in NBPP knowledge.RESULTS:Of the 273 surveys collected, 45% were from referring providers and 55% were from treating providers. Saudi Arabian and North American HCPs demonstrated similar NBPP knowledge except for potential etiologies for NBPP and surgery timing. In North America, referring and treating providers had similar overall knowledge of NBPP but lacked familiarity with its natural history. A knowledge gap existed between academic and community hospitals regarding timing of referral/initiation of physical/occupational therapy (PT/OT) and Horner's syndrome. Providers with self-reported confidence in treating NBPP had greater knowledge of types of NBPP and timing for PT/OT initiation.CONCLUSIONS:Overall, North American providers demonstrated adequate knowledge of NBPP. However, both eastern and western physicians remain overly optimistic in believing that most infants recover spontaneously. This study revealed a unique and universal knowledge gap in NBPP diagnosis, referral, and management worldwide. Continuous efforts to increase NBPP knowledge are indicated.

Background: A longstanding dictum exists to avoid surgical manipulation of the temporalis muscle out of concern for an exceedingly high rate of muscle atrophy and recurrent temporal hollowing. The authors challenge this surgical myth, considering such advice to be erroneous. The authors hypothesize that elevation of the temporalis muscle, if performed using standard muscle flap principles, will demonstrate excellent results. Methods: To assess temporalis response to surgical manipulation, the authors reviewed patients who underwent calvarial vault remodeling by the senior author for craniosynostosis between 1988 and 2011. Nonsyndromic patients with single-suture synostosis and 5 years of follow-up were eligible for inclusion. The medical record was used to measure rates of reoperation, recurrent temporal hollowing, and persistent temporalis overcorrection. Results: Of the cohort reviewed, 196 patients met inclusion criteria. Ten patients (5.1%) exhibited recurrent bitemporal constriction. One patient (0.5%) underwent a revision temporalis turnover flap, and 2 patients (1.0%) underwent soft tissue augmentation. The overall reoperation rate was 1.5%. Temporalis overcorrection, in an attempt to prophylactically rectify the expected atrophy after temporalis manipulation, persisted in 11 patients (5.6%). Three of these patients required treatment with steroid injections, Botox injections, or operative muscle debulking. The overall reoperation rate for temporalis overcorrection was 1.5%. Conclusions: The authors’ low reoperation rates for recurrent deformity, in combination with persistent temporalis overcorrection in 5.6% of patients, should dispel the myth that manipulation of the temporalis invariably results in atrophy. The muscle may be surgically manipulated, as long as plastic surgery principles are followed.